tbuckley/cabot-search huggingface dataset:
Real-time Analysis of Skin Biopsy Specimens With 2-Photon Fluorescence Microscopy
Authors: Vincent D. Ching-Roa, Chi Z. Huang, Sherrif F. Ibrahim, Bruce R. Smoller, Michael G. Giacomelli
Journal: JAMA Dermatology (2022)

Importance Nonmelanoma skin cancers (NMSCs) are primarily diagnosed through paraffin section histologic analysis of skin biopsy specimens that requires days to weeks before a formal diagnosis is reported. Two-photon fluorescence microscopy (TPFM) has the potential for point-of-care diagnosis of NMSC and other dermatologic conditions, which could enable same-visit diagnosis and treatment. Objective To demonstrate that TPFM imaging of NMSC can occur within minutes of obtaining biopsies and provide similar histological features to those of conventional histology and evaluate TPFM diagnostic performance with respect to conventional histology. Design, Setting, and Participants This comparative effectiveness pilot study examined 29 freshly excised biopsies from confirmed NMSC lesions in patients presenting for treatment. Biopsies underwent imaging immediately with TPFM on site at Rochester Dermatologic Surgery (Victor, New York) between October 2019 and August 2021. The imaged biopsies were subsequently submitted for paraffin histology to produce coregistered images. Twelve of these coregistered image pairs (41.4%) were used as a training set. Fifteen (51.7%) were used in a masked evaluation by a board-certified dermatopathologist. Two (6.9%) were excluded from the study before evaluation because they could not be coregistered. Main Outcomes and Measures Sensitivity, specificity, and accuracy of TPFM for NMSC biopsies were evaluated compared with conventional histology. Results Fourteen of the 15 biopsy specimens (93.3%) in the evaluation set were identically diagnosed with TPFM and paraffin histology. The TPFM had 100% sensitivity (95% CI, 48%-100%), 100% specificity (95% CI, 69%-100%), and 100% accuracy (95% CI, 78%-100%) for basal cell carcinoma diagnosis. For squamous cell carcinoma diagnosis, TPFM had 89% sensitivity (95% CI, 52%-100), 100% specificity (95% CI, 54%-100%), and 93% accuracy (95% CI, 68%-100%). For overall NMSC diagnosis, TPFM had a 93% sensitivity (95% CI, 66%-100%), 100% specificity (95% CI, 3%-100%), and 93% accuracy (95% CI, 68%-100%). Examination of the 1 discordant pair revealed mismatched imaging planes as the source of error. Conclusions and Relevance The results of this comparative effectiveness pilot study suggest that TPFM captures histological characteristics of NMSC that are present in conventional histology, which reveals its potential as a rapid, point-of-care diagnostic alternative that does not need extensive sample preparation or retraining for image evaluation. Further validation of TPFM imaging performed for a larger cohort is needed to fully evaluate its diagnostic accuracy and potential effect within the field.
Sex-Adjusted Model for End-stage Liver Disease Scores for Liver Transplant Allocation
Authors: Nicholas L. Wood, Dorry L. Segev, Sommer E. Gentry
Journal: JAMA Surgery (2022)

To the Editor Sealock et al1 used novel data to explore a known problem: the sodium-adjusted Model for End-stage Liver Disease (MELDNa) score underestimates disease severity for female individuals awaiting a liver transplant. Their proposed solution would overcorrect the MELDNa score.
GPX4 regulates cellular necrosis and host resistance in <i>Mycobacterium tuberculosis</i> infection
Authors: Eduardo P. Amaral, Taylor W. Foreman, Sivaranjani Namasivayam, Kerry L. Hilligan, Keith D. Kauffman, Caio Cesar Barbosa Bomfim, Diego L. Costa, Beatriz Barreto-Duarte, Clarissa Gurgel-Rocha, Monique Freire Santana, Marcelo Cordeiro-Santos, Elsa Du Bruyn, Catherine Riou, Kate Aberman, Robert John Wilkinson, Daniel L. Barber, Katrin D. Mayer-Barber, Bruno B. Andrade, Alan Sher
Journal: The Journal of Experimental Medicine (2022)

Cellular necrosis during Mycobacterium tuberculosis (Mtb) infection promotes both immunopathology and bacterial dissemination. Glutathione peroxidase-4 (Gpx4) is an enzyme that plays a critical role in preventing iron-dependent lipid peroxidation–mediated cell death (ferroptosis), a process previously implicated in the necrotic pathology seen in Mtb-infected mice. Here, we document altered GPX4 expression, glutathione levels, and lipid peroxidation in patients with active tuberculosis and assess the role of this pathway in mice genetically deficient in or overexpressing Gpx4. We found that Gpx4-deficient mice infected with Mtb display substantially increased lung necrosis and bacterial burdens, while transgenic mice overexpressing the enzyme show decreased bacterial loads and necrosis. Moreover, Gpx4-deficient macrophages exhibited enhanced necrosis upon Mtb infection in vitro, an outcome suppressed by the lipid peroxidation inhibitor, ferrostatin-1. These findings provide support for the role of ferroptosis in Mtb-induced necrosis and implicate the Gpx4/GSH axis as a target for host-directed therapy of tuberculosis.
Functional role of endothelial transferrin receptor 1 in iron sensing and homeostasis
Authors: Allison L. Fisher, Chia‐yu Wang, Yang Xu, Kole Joachim, Xia Xiao, Sydney Phillips, Gillian A. Moschetta, Victor M. Alfaro‐Magallanes, Jodie L. Babitt
Journal: American Journal of Hematology (2022)

Abstract Systemic iron homeostasis is regulated by the hepatic hormone hepcidin to balance meeting iron requirements while limiting toxicity from iron excess. Iron‐mediated induction of bone morphogenetic protein (BMP) 6 is a central mechanism for regulating hepcidin production. Liver endothelial cells (LECs) are the main source of endogenous BMP6, but how they sense iron to modulate BMP6 transcription and thereby hepcidin is uncertain. Here, we investigate the role of endothelial cell transferrin receptor 1 (TFR1) in iron uptake, BMP6 regulation, and systemic iron homeostasis using primary LEC cultures and endothelial Tfrc (encoding TFR1) knockout mice. We show that intracellular iron regulates Bmp6 expression in a cell‐autonomous manner, and TFR1 mediates iron uptake and Bmp6 expression by holo‐transferrin in primary LEC cultures. In addition, endothelial Tfrc knockout mice exhibit altered iron homeostasis compared with littermate controls when fed a limited iron diet, as evidenced by increased liver iron and inappropriately low Bmp6 and hepcidin expression relative to liver iron. However, endothelial Tfrc knockout mice have a similar iron phenotype compared to littermate controls when fed an iron‐rich standard diet. Finally, ferritin and non‐transferrin bound iron (NTBI) are additional sources of iron that mediate Bmp6 induction in primary LEC cultures via TFR1‐independent mechanisms. Together, our data demonstrate a minor functional role for endothelial cell TFR1 in iron uptake, BMP6 regulation, and hepatocyte hepcidin regulation under iron limiting conditions, and suggest that ferritin and/or NTBI uptake by other transporters have a dominant role when iron availability is high.
VRK1 Is a Synthetic–Lethal Target in VRK2-Deficient Glioblastoma
Authors: Julie A. Shields, Samuel R. Meier, Madhavi Bandi, Erin E. Mulkearns-Hubert, Nicole Hajdari, Maria Dam Ferdinez, Justin L. Engel, Daniel J. Silver, Binzhang Shen, Wenhai Zhang, Christopher G. Hubert, Kelly Mitchell, Sajina Shakya, Shan-Chuan Zhao, Alborz Bejnood, Minjie Zhang, Robert Tjin Tham Sjin, Erik Wilker, Justin D. Lathia, Jannik N. Andersen, Yingnan Chen, Fang Li, Barbara Weber, Alan Huang, Natasha Emmanuel
Journal: Cancer Research (2022)

Abstract Synthetic lethality is a genetic interaction that results in cell death when two genetic deficiencies co-occur but not when either deficiency occurs alone, which can be co-opted for cancer therapeutics. Pairs of paralog genes are among the most straightforward potential synthetic–lethal interactions by virtue of their redundant functions. Here, we demonstrate a paralog-based synthetic lethality by targeting vaccinia-related kinase 1 (VRK1) in glioblastoma (GBM) deficient of VRK2, which is silenced by promoter methylation in approximately two thirds of GBM. Genetic knockdown of VRK1 in VRK2-null or VRK2-methylated cells resulted in decreased activity of the downstream substrate barrier to autointegration factor (BAF), a regulator of post-mitotic nuclear envelope formation. Reduced BAF activity following VRK1 knockdown caused nuclear lobulation, blebbing, and micronucleation, which subsequently resulted in G2–M arrest and DNA damage. The VRK1–VRK2 synthetic–lethal interaction was dependent on VRK1 kinase activity and was rescued by ectopic expression of VRK2. In VRK2-methylated GBM cell line–derived xenograft and patient-derived xenograft models, knockdown of VRK1 led to robust tumor growth inhibition. These results indicate that inhibiting VRK1 kinase activity could be a viable therapeutic strategy in VRK2-methylated GBM. Significance: A paralog synthetic–lethal interaction between VRK1 and VRK2 sensitizes VRK2-methylated glioblastoma to perturbation of VRK1 kinase activity, supporting VRK1 as a drug discovery target in this disease.
Artificial Pancreas and Expanding the Use of Total Pancreatectomy
Authors: Ville Sallinen, Pauli Puolakkainen
Journal: JAMA Surgery (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Allergic disease trajectories up to adolescence: Characteristics, early‐life, and genetic determinants
Authors: Anna Kilanowski, Elisabeth Thiering, Gang Wang, Ashish Kumar, Sara Kress, Claudia Flexeder, Carl‐Peter Bauer, Dietrich Berdel, Andrea von Berg, Anna Bergström, Monika Gappa, Joachim Heinrich, Gunda Herberth, Sibylle Koletzko, Inger Kull, Erik Melén, Tamara Schikowski, Annette Peters, Marie Standl
Journal: Allergy (2022)

Allergic diseases often develop jointly during early childhood but differ in timing of onset, remission, and progression. Their disease course over time is often difficult to predict and determinants are not well understood.We aimed to identify trajectories of allergic diseases up to adolescence and to investigate their association with early-life and genetic determinants and clinical characteristics.Longitudinal k-means clustering was used to derive trajectories of allergic diseases (asthma, atopic dermatitis, and rhinitis) in two German birth cohorts (GINIplus/LISA). Associations with early-life determinants, polygenic risk scores, food and aeroallergen sensitization, and lung function were estimated by multinomial models. The results were replicated in the independent Swedish BAMSE cohort.Seven allergic disease trajectories were identified: "Intermittently allergic," "rhinitis," "early-resolving dermatitis," "mid-persisting dermatitis," "multimorbid," "persisting dermatitis plus rhinitis," and "early-transient asthma." Family history of allergies was more prevalent in all allergic disease trajectories compared the non-allergic controls with stronger effect sizes for clusters comprising more than one allergic disease (e.g., RRR = 5.0, 95% CI = [3.1-8.0] in the multimorbid versus 1.8 [1.4-2.4] in the mild intermittently allergic cluster). Specific polygenic risk scores for single allergic diseases were significantly associated with their relevant trajectories. The derived trajectories and their association with genetic effects and clinical characteristics showed similar results in BAMSE.Seven robust allergic clusters were identified and showed associations with early life and genetic factors as well as clinical characteristics.
Breast cancer screening during the COVID-19 pandemic: moving from disparities to health equity
Authors: Ilana Richman, Baylah Tessier-Sherman, Deron Galusha, Carol R Oladele, Karen Wang
Journal: JNCI Journal of the National Cancer Institute (2022)

Abstract The COVID-19 pandemic created unprecedented disruptions to routine health care in the United States. Screening mammography, a cornerstone of breast cancer control and prevention, was completely halted in the spring of 2020, and screening programs have continued to face challenges with subsequent COVID-19 waves. Although screening mammography rates decreased for all women during the pandemic, a number of studies have now clearly documented that reductions in screening have been greater for some populations than others. Specifically, minoritized women have been screened at lower rates than White women across studies, although the specific patterns of disparity vary depending on the populations and communities studied. We posit that these disparities are likely due to a variety of structural and contextual factors, including the differential impact of COVID-19 on communities. We also outline key considerations for closing gaps in screening mammography. First, practices, health systems, and communities must measure screening mammography use to identify whether gaps exist and which populations are most affected. Second, we propose that strategies to close disparities in breast cancer screening must be multifaceted, targeting the health system or practice, but also structural factors at the policy level. Health disparities arise from a complex set of conditions, and multimodal solutions that address the complex, multifactorial conditions that lead to disparities may be more likely to succeed and are necessary for promoting health equity.
ALKBH5-Mediated m6A Demethylation of GLUT4 mRNA Promotes Glycolysis and Resistance to HER2-Targeted Therapy in Breast Cancer
Authors: Hao Liu, Hui Lyu, Guanmin Jiang, Danyang Chen, Sanbao Ruan, Shuang Liu, Lukun Zhou, Minqiang Yang, Shanshan Zeng, Zhimin He, Hongsheng Wang, Hongsheng Li, Guopei Zheng, Bolin Liu
Journal: Cancer Research (2022)

Abstract Resistance to HER2-targeted therapy represents a significant challenge for the successful treatment of patients with breast cancer with HER2-positive tumors. Through a global mass spectrometry–based proteomics approach, we discovered that the expression of the N6-methyladenosine (m6A) demethylase ALKBH5 was significantly upregulated in HER2-targeted therapy-resistant breast cancer cells. Elevated expression of ALKBH5 was sufficient to confer resistance to HER2-targeted therapy, and specific knockdown of ALKBH5 rescued the efficacy of trastuzumab and lapatinib in resistant breast cancer cells. Mechanistically, ALKBH5 promoted m6A demethylation of GLUT4 mRNA and increased GLUT4 mRNA stability in a YTHDF2-dependent manner, resulting in enhanced glycolysis in resistant breast cancer cells. In breast cancer tissues obtained from patients with poor response to HER2-targeted therapy, increased expression of ALKBH5 or GLUT4 was observed and was significantly associated with poor prognosis in the patients. Moreover, suppression of GLUT4 via genetic knockdown or pharmacologic targeting with a specific inhibitor profoundly restored the response of resistant breast cancer cells to trastuzumab and lapatinib, both in vitro and in vivo. In conclusion, ALKBH5-mediated m6A demethylation of GLUT4 mRNA promotes resistance to HER2-targeted therapy, and targeting the ALKBH5/GLUT4 axis has therapeutic potential for treating patients with breast cancer refractory to HER2-targeted therapies. Significance: GLUT4 upregulation by ALKBH5-mediated m6A demethylation induces glycolysis and resistance to HER2-targeted therapy and represents a potential therapeutic target for treating HER2-positive breast cancer.
Association of Residual Ductal Carcinoma In Situ With Breast Cancer Recurrence in the Neoadjuvant I-SPY2 Trial
Authors: Marie Osdoit, Christina Yau, W. Fraser Symmans, Judy C. Boughey, Cheryl A. Ewing, Ron Balassanian, Yunn-Yi Chen, Gregor Krings, Anne M Wallace, Somaye Zare, Oluwole Fadare, Rachael Lancaster, Shi Wei, Constantine V. Godellas, Ping Tang, Todd M Tuttle, Molly Klein, Sunati Sahoo, Tina J. Hieken, Jodi M. Carter, Beiyun Chen, Gretchen Ahrendt, Julia Tchou, Michael Feldman, Eleni Tousimis, Jay Zeck, Nora Jaskowiak, Husain Sattar, Arpana M. Naik, Marie Catherine Lee, Marilin Rosa, Laila Khazai, Mara H. Rendi, Julie E. Lang, Janice Lu, Ossama Tawfik, Smita M. Asare, Laura J. Esserman, Rita A. Mukhtar
Journal: JAMA Surgery (2022)

Pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in breast cancer strongly correlates with overall survival and has become the standard end point in neoadjuvant trials. However, there is controversy regarding whether the definition of pCR should exclude or permit the presence of residual ductal carcinoma in situ (DCIS).To examine the association of residual DCIS in surgical specimens after neoadjuvant chemotherapy for breast cancer with survival end points to inform standards for the assessment of pathologic complete response.The study team analyzed the association of residual DCIS after NAC with 3-year event-free survival (EFS), distant recurrence-free survival (DRFS), and local-regional recurrence (LRR) in the I-SPY2 trial, an adaptive neoadjuvant platform trial for patients with breast cancer at high risk of recurrence. This is a retrospective analysis of clinical specimens and data from the ongoing I-SPY2 adaptive platform trial of novel therapeutics on a background of standard of care for early breast cancer. I-SPY2 participants are adult women diagnosed with stage II/III breast cancer at high risk of recurrence.Participants were randomized to receive taxane and anthracycline-based neoadjuvant therapy with or without 1 of 10 investigational agents, followed by definitive surgery.The presence of DCIS and EFS, DRFS, and LRR.The study team identified 933 I-SPY2 participants (aged 24 to 77 years) with complete pathology and follow-up data. Median follow-up time was 3.9 years; 337 participants (36%) had no residual invasive disease (residual cancer burden 0, or pCR). Of the 337 participants with pCR, 70 (21%) had residual DCIS, which varied significantly by tumor-receptor subtype; residual DCIS was present in 8.5% of triple negative tumors, 15.6% of hormone-receptor positive tumors, and 36.6% of ERBB2-positive tumors. Among those participants with pCR, there was no significant difference in EFS, DRFS, or LRR based on presence or absence of residual DCIS.The analysis supports the definition of pCR as the absence of invasive disease after NAC regardless of the presence or absence of DCIS.ClinicalTrials.gov Identifier NCT01042379.
Tumor‐associated macrophages in liver cancer: From mechanisms to therapy
Authors: Kun Cheng, Ning Cai, Jinghan Zhu, Xing Yang, Huifang Liang, Wanguang Zhang
Journal: Cancer Communications (2022)

Abstract Multidimensional analyses have demonstrated the presence of a unique tumor microenvironment (TME) in liver cancer. Tumor‐associated macrophages (TAMs) are among the most abundant immune cells infiltrating the TME and are present at all stages of liver cancer progression, and targeting TAMs has become one of the most favored immunotherapy strategies. In addition, macrophages and liver cancer cells have distinct origins. At the early stage of liver cancer, macrophages can provide a niche for the maintenance of liver cancer stem cells. In contrast, cancer stem cells (CSCs) or poorly differentiated tumor cells are key factors modulating macrophage activation. In the present review, we first propose the origin connection between precursor macrophages and liver cancer cells. Macrophages undergo dynamic phenotypic transition during carcinogenesis. In this course of such transition, it is critical to determine the appropriate timing for therapy and block specific markers to suppress pro‐tumoral TAMs. The present review provides a more detailed discussion of transition trends of such surface markers than previous reviews. Complex crosstalk occurs between TAMs and liver cancer cells. TAMs play indispensable roles in tumor progression, angiogenesis, and autophagy due to their heterogeneity and robust plasticity. In addition, macrophages in the TME interact with other immune cells by directing cell‐to‐cell contact or secreting various effector molecules. Similarly, tumor cells combined with other immune cells can drive macrophage recruitment and polarization. Despite the latest achievements and the advancements in treatment strategies following TAMs studies, comprehensive discussions on the communication between macrophages and cancer cells or immune cells in liver cancer are currently lacking. In this review, we discussed the interactions between TAMs and liver cancer cells (from cell origin to maturation), the latest therapeutic strategies (including chimeric antigen receptor macrophages), and critical clinical trials for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) to provide a rationale for further clinical investigation of TAMs as a potential target for treating patients with liver cancer.
In-Person Medical Conferences During the COVID-19 Pandemic
Authors: Winfried V. Kern, Daniel J. Morgan
Journal: JAMA Network Open (2022)

Casey M. Silver, MD; Rachel H. Joung, MD; Melanie S. Morris, MD; Kasper S. Wang, MD; Amir A. Ghaferi, MD, MS; Karl Y. Bilimoria, MD, MS; Callisia N. Clarke, MD, MS